NEUROIMMUNOLOGY TAKES WING
JOHN NEWSOM-DAVIS, MD
In October 2002, John Newsom-Davis, MD, reunited with some old friends and colleagues in Worcestershire, England. These friends were not neurologists – they were pilots, the survivors of the Wings course he took 50 years ago to become a Royal Air Force (RAF) Pilot. “We celebrated at a hostelry in Worcestershire (in true RAF style, of course),” he recalled. “Next day we visited the airfield where we trained, and, like overgrown schoolboys, drove at speed down the runway in formation, our partners holding on to their seats, eyes tightly closed.”
A lot of things might have kept Dr. Newsom-Davis from a career in neurology in general and neuroimmunology in particular. As a young man, he had no interest in science. He studied history and English in school, and had a place at Cambridge to read English when he decided that flying might be a better way to spend his compulsory National Service than life in the trenches.
“I started training in an open cockpit biplane Tiger Moth, a throwback to the 1930s, when it was designed. I ended flying one of the early jets, the Meteor MkIV.”
While flying – or while waiting for the fog to clear – Dr. Newsom-Davis found himself with lots of time to reflect. “My grandfather, who died when I was quite young, had been a doctor, and my mother encouraged me, though I was full of doubts,” he said. “I started reading biology in the evenings, and found I liked it.” So instead of going back to his place at Cambridge upon leaving the RAF, he spent nine months at a London tutorial college to get up to speed “from a standing start” in physics, chemistry, botany, and zoology.
THE ‘NEUROLOGICAL LIGHT’
Cambridge then agreed to accept him for a degree in natural sciences instead of English. That might seem unremarkable for the average American college student, who changes majors more often than changing socks, but it is not so easy in Britain. “In the UK, students now have to decide at the age of 15 or so what direction to take in their career; I was lucky to be able to make my choice much later,” Dr. Newsom-Davis said.
Entering his clinical training at Middlesex Hospital Medical School in London, Dr. Newsom-Davis thought he might pursue psychiatry. “Who isn't interested in that in their early twenties?” he asked. But he “saw the neurological light” as a student and later houseman (intern) in his neurology rotation with Michael Kremer and Roger Gilliatt.
“I had become increasingly uneasy at the prospect of launching my little canoe into the psychiatric ocean with so many confusing landmarks,” he recalled. “Gilliatt was initially extremely supportive of a career in neurology for me, until he discovered that I was much older than I appeared – 30 by then,” he recalled. “Since his own considerable achievements were obtained at an early age, he concluded that I was over the top and suggested a career in industrial medicine. Nothing wrong in that, of course, but not exactly what I wanted.”
Dr. Newsom-Davis was not to be dissuaded. His burgeoning interest in research was kindled by E.J. Moran Campbell, then the First Assistant on the Professorial Medical unit at Middlesex Hospital, who led him to a position studying with neurophysiologist Tom Sears, “a marvelous teacher with strong interests in respiration,” at the Institute of Neurology, Queen Square.
FROM NEUROPHYSIOLOGY TO NEUROIMMUNOLOGY
After a postgraduate stint as a research fellow with the “towering figure” Fred Plum at Cornell, Dr. Newsom-Davis returned to England and a consulting neurology appointment at the Royal Free Hospital in London that came with a joint position at Queen Square. There, he continued to pursue his interest in neurophysiology – until a series of events set him on a very different path.
“I was developing a method for recording from human intercostal muscle spindles in vitro. This required my dissecting a small piece of intercostal muscle from patients undergoing chest surgery, with impatient thoracic surgeons breathing down my neck,” he recalled. “Mastering this tricky technique was inadvertently the first event that led to my subsequent interest in disorders of neuromuscular transmission. Nobel Prize winner Bernard (now Sir Bernard) Katz and his colleague Ricardo Miledi, renowned for their basic science work in this field, wanted to study the human neuromuscular junction.”
Drs. Katz and Miledi asked Dr. Newsom-Davis if he could obtain an intercostal muscle biopsy for them. “It was in the early 1970s when alpha-bungarotoxin was first being used to study acetylcholine receptors. I was privileged to see Katz and Miledi undertaking an experiment together on the muscle that I had biopsied,” he said.
Not long after, Dr. Newsom-Davis found himself caring for a myasthenia gravis patient in the Queen Square ICU, who had been frequently readmitted due to respiratory failure. “By then, AChR antibodies had been discovered in myasthenia gravis patients, and the technique of plasmapheresis had just begun to be used in antibody-mediated kidney disease at the Hammersmith Hospital,” he recalled. “We plasma exchanged (plasmapheresed) our patient, resulting in her dramatic improvement.” The results, which appeared in a 1976 paper in The Lancet, took Dr. Newsom-Davis in yet another new direction.
“The patient's dramatic, though temporary, recovery caused me to redirect my research career from neurophysiology to neuroimmunology,” he said. “Immunology had moved on in the ten years since I had been at Cambridge, so I went to evening classes to retrain in the new discipline.”
He established a research partnership with Angela Vincent, at the time a junior research assistant to Katz and Miledi, in a quest for a project grant to study myasthenia gravis – a partnership that continues to this day.
A TEAM APPROACH
The switch from neurophysiology to neuroimmunology was a high-risk strategy – although former RAF pilots might measure risk in a different way than the rest of us. “I was then in my mid-forties, and I had a lot of ground to catch up on,” Dr. Newsom-Davis said. “But it was absolutely crucial to my subsequent career, because the field has proved to be so fertile.”
He attributes much of his success in that fertile field to a team approach. “Our team has now been together for over 20 years, which has been crucial to our studies of antibody-mediated and genetic channelopathies.” Building on its discoveries in myasthenia gravis, Dr. Newsom-Davis's team moved on to the Lambert-Eaton myasthenic syndrome, showing that it is mediated by calcium channel antibodies, and to neuromyotonia, demonstrating that it is mediated by antibodies to potassium channels.
He discussed three of his latest targets at the AAN Annual Meeting in the Robert Wartenburg Lecture on “Antibody-Mediated Channelopathies at the Neuromuscular Junction and Beyond: New Targets, New Syndromes.”
“First, antibodies to MuSK seem to associate with a distinct phenotype in young females,” he explained. “Second, antibodies to cerebellar voltage-gated calcium channels may explain the ataxia sometimes seen in the Lambert-Eaton myasthenic syndrome. Finally, antibodies to voltage-gated potassium channels, in addition to causing peripheral nerve hyperexcitability, may be implicated in limbic encephalitis.”
Experts in neuromuscular disease, immunology, and oncology recognize John Newsom-Davis as a major figure in all of these fields. His broad interests and leadership make him an ideal choice to be the Editor of Brain and to have been the Robert Wartenberg Lecturer.